As48是一流的双功能TREM2调制器:受体激活和脱落抑制
Sungwoo Cho1, Farida El Gaamouch1, Saurabh Upadhyay1
1Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, NY 10065, USA.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
|December 3, 2025
概括
一种新的小分子,As48,激活TREM2信号,并增强微质细胞化. 它还可以防止TREM2受体脱离,为阿尔茨海默氏症神经炎症提供了一种新的治疗策略.
科学领域:
- 神经科学是一个神经科学.
- 免疫学 免疫学 免疫学
- 药理学 药理学是指药理学的学科.
背景情况:
- 在骨髓细胞2 (TREM2) 上表达的触发受体功能障碍与阿尔茨海默氏症 (AD) 病原发生有关.
- 目前的AD治疗方法没有解决ADAM介导的TREM2受体脱落,从而降低了信号的有效性.
研究的目的:
- 确定调节TREM2活动的新型小分子.
- 通过检查其对TREM2激活和脱落的影响来研究As48作为AD治疗剂的潜力.
主要方法:
- 亲和选择质谱 (AS-MS) 查以确定TREM2结合剂.
- 生物物理验证,细胞检测 (SYK酸化,微质细胞化),分子对接和分子动力学模拟.
- 评估As48对TREM2ectodomain脱落和ADAM10/17蛋白酶活性的影响.
主要成果:
- As48被确定为一种高亲缘关系的TREM2结合剂,对TREM1具有很高的选择性.
- As48表现出TREM2的激动性,增强微质细胞化和SYK酸化.
- 在不影响ADAM10/17活动的情况下,As48通过对蛋白酶的可访问性进行结构性限制来抑制TREM2脱落.
- As48表现出有利的药理动力学,具有大脑透性的潜力.
结论:
- As48是第一个通过形状限制抑制TREM2脱落的小分子.
- As48促进TREM2激活和防止脱落的双重作用为AD中神经炎症提供了一种新的治疗方法.
- As48显示了对阿尔茨海默病药物发现的翻译相关性.
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